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Establishment of reference values for endocrine tests--part V: acromegaly.

BACKGROUND: Plasma insulin-like growth factor 1 (IGF-1) and the response of growth hormone (GH) to oral glucose are frequently used in the evaluation of patients suspected of acromegaly. Because of the implementation of new assay methodology for GH and IGF-1, we have established the reference values for these tests, as well as for urinary GH excretion. METHODS: From the general population, 50 subjects were recruited, equally distributed according to sex and age between 20 and 70 years. Two consecutive 24-hour urine samples were collected to determine urinary GH. Plasma IGF-1 was measured as well as the GH response during an oral glucose tolerance test (OGTT) with 100 g glucose. Basal plasma IGF-1 was also measured in 250 subjects recruited likewise from the general population who had participated in previous studies on reference values. RESULTS: The following reference ranges were established: urinary GH < 5-46 microU/24 h; nadir GH after OGTT < or =1.5 mU/l for males and < or =2.0 mU/l for females. IGF-1 was divided into age groups: 20-30 years 8-61 nmol/l; 31-40 years 8-41 nmol/; 41-50 years 7-36 nmol/l; 51-60 years 5-37 nmol/l; and 61-70 years 7-27 nmol/l. CONCLUSION: We have established reference values with state-of-the-art assay methodology for the diagnostic tests frequently used in the evaluation of patients suspected of acromegaly.

Acromegaly↗

[Is the early diagnosis of a pancreatic neoplasm possible? A report and comparison of 2 clinical cases].

Following a critical review of the international literature on the subject of cancer of the pancreas, the authors report two case studies of this pathology, one of which was diagnosed at a preclinical stage and underwent radical surgical exeresis. The authors draw attention to two factors which must be taken into consideration in this pathology: firstly, the need to extend screening tests in the group of high-risk patients, above all in those who drink three or more cups of coffee a day; secondly, to re-evaluate the diagnostic use of two hematochemical tests, lipasemia and amylasemia, which are easily performed and available in all clinical laboratories.

Amylases↗

Premalignant breast lesions: role for biological markers in predicting progression to cancer.

Biological markers associated with in situ carcinoma and atypical intraductal hyperplasia in the breast are examined to help in identifying a subgroup of premalignant lesions whose natural history may be influenced by epigenetic factors. The biomarkers may be used as indices in clinical trials aiming to assess the effect of weight reduction, dietary intervention or hormone replacement therapy on the risk of progression to invasive breast cancer. In the current state of knowledge, the expression of oestrogen receptors, p53, bcl-2 and HER-2 neu oncogenes and the Ki-67 index of proliferative activity, are the most useful biomarkers for this purpose. In situ carcinoma of the breast manifests a variety of morphological phenotypes with specific biological characteristics. There is evidence that only a proportion of premalignant lesions are committed to progression to invasive cancer while other lesions undergo spontaneous regression at the time of the menopause. Cross-cultural studies suggest that it is the late-stage epigenetic promoting factors which are responsible for the high incidence of postmenopausal breast cancer in Western women. Obesity in middle life and the Western diet favour the development of hyperinsulinaemic insulin resistance, and the metabolic-endocrine effects of its concomitants may promote mammary carcinogenesis around the time of the menopause and increase the incidence of invasive cancer after the menopause. Because biomarker changes in premalignant lesions are nearer in time to these promoting influences, they could provide intermediate endpoints for testing the hypothesis.

Adult↗

Trichomonas vaginalis P16 Immunoreactivity in cervicovaginal Pap tests: a diagnostic pitfall.

Detection of p16 is emerging as a useful biomarker for Human Papillomavirus (HPV)-related dysplastic and malignant lesions of the cervix, and as such has potential application to cervicovaginal Papanicolaou (Pap) specimens. While evaluating p16 immunocytochemistry in our laboratory we observed one Pap test in which Trichomonas vaginalis stained positively for p16. We therefore proceeded to determine the frequency of T. vaginalis immunoreactivity for p16 in 10 consecutive, satisfactory, liquid-based Pap tests diagnosed as negative for intraepithelial lesion or malignancy in which T. vaginalis was present. For each case, a ThinPrep slide prepared from residual vial material was immunostained with p16. In an additional case, a prepared cell block was stained with p16. T. vaginalis were consistently p16 positive. We document, for the first time, p16 immunoreactivity of T. vaginalis that, on a Pap slide and cell block, may be morphologically misinterpreted as small dysplastic or malignant epithelial cells. The presence of this parasite in Pap tests may also potentially hinder the use of p16 as an adjunct to liquid-based cervical screening cytology.

Adolescent↗

Host factors in occupational diisocyanate asthma: a Swiss longitudinal study.

OBJECTIVE: To investigate the usefulness of surrogates for individual susceptibility to organic diisocyanates in occupational asthma. SUBJECTS: All new cases declared to the Swiss National Accident Insurance Company (SUVA) for establishment of a case for compensable occupational disease during 1993. Sixty-nine persons, of whom three were women, were suspected of having occupational asthma due to isocyanates. Of these, 47 subjects fulfilled the criteria to be accepted as an occupational disease case. METHODS: All subjects were studied clinically and gave a blood sample for the phenotyping of their alpha-antitrypsin status and for immunological studies. The subjects were also given a peroral dose of caffeine for the determination of their N-acetylation capacity. Finally, those with an occupational disease were subjected to the methacholine provocation test. RESULTS: Forty-four persons with occupational disease, out of 47, were heterozygous antitrypsin carriers and/or slow acetylators of primary amines. In the bronchial provocation with methacholine, 12 of these subjects had an unaltered response and seven had a mild reaction, 13 a moderate one and 15 a severe reaction. INTERPRETATION: The study confirms the finding that slow N-acetylators are susceptible to asthma from exposure to common diisocyanate monomers at work. The same applies to heterozygous antitrypsin-phenotype carriers. Thus, the use of these markers may reinforce the diagnostic procedure, but they cannot completely replace the immunological tests.

Adult↗

Introduction of cAMP and establishment of neutral lipids alterations as pollution biomarkers using the mussel Mytilus galloprovincialis. Correlation with a battery of biomarkers.

The results of the present study suggest that the signaling molecule cAMP could constitute a reliable biomarker of pollution monitoring. Increased levels of cAMP were observed in tissues of mussels Mytilus galloprovincialis exposed to PAHs, 2,4-dichlorophenoxyacetic acid and lindane for 15 days. cAMP levels were higher in mantle/gonad complex, in relation to other tissues studied (digestive gland and gills). In support of our suggestion, cAMP was significantly correlated with established biomarkers, such as lysosomal membrane stability, AChE activity and metallothionein content. In addition, our results support the establishment of morphometrical alterations of neutral lipids as biomarker of organic pollution, since high accumulation of neutral lipids in the digestive gland of mussels exposed to organic pollutants in relation to non-exposed mussels was noted. In addition, correlation analysis between cellular and biochemical biomarkers showed that the volume density of neutral lipids negatively correlated with both lysosomal membrane stability and AChE activity. Regarding micronucleus test, our results do not support its use as a biomarker of organic pollution, since no statistical differences were found between control and exposed mussels. On the other hand, significant correlations were observed among the battery of biomarkers, such as lysosomal membrane stability, AChE activity and metallothionein content after the mussels' exposure to the specific organic compounds, thus supporting the important role of these biomarkers as reliable indicators of organic pollution. In conclusion, our results support cAMP and morphometrical alterations of neutral lipids as biomarkers of environmental pollution.

2,4-Dichlorophenoxyacetic Acid↗

Neuro-endocrine biomarkers of pollution-induced stress in marine invertebrates.

Nitric oxide (NO) is a molecular mediator of the non-specific immune response of vertebrates but production has also been recorded in response to bacterial infection in invertebrates. Together with biogenic amines and cytokines, production of NO in invertebrate phagocytic haemocytes is thought to represent a putative stress response. In this study the hypothesis that NO might be a sensitive biomarker of stress in invertebrates has been tested. The spectrophotometric Griess assay for nitrite and nitrate has been modified so that the final breakdown products of NO are suitable for measurement in invertebrate haemolymph. The assay was linear in the range 1-100 microM with a sensitivity of 4 microM. The baseline NOx measurement in unstressed mussels was 0.74 mM NOx/mg protein. Mytilus edulis were kept at 15 micro C in filtered seawater for at least 2 days prior to exposure to TBTO (0.001-0.1 mg/l) for 24 h. Preliminary results suggest that TBTO perturbs the NO response and that the outlined assay protocol is a sensitive means of detecting those changes. It is proposed that NO measurements potentially offer a highly sensitive, non-invasive means of monitoring stress responses associated with environmental change.

Adaptation, Physiological↗

Prognostic value of combined use of biomarkers of inflammation, endothelial dysfunction, and myocardiopathy in patients with ESRD.

BACKGROUND: Cardiovascular risk stratification is important in the clinical management of patients with end-stage renal diseases (ESRD) and biomarkers are increasingly used in these patients. METHODS: In a cohort of 246 dialysis patients without heart failure at baseline we tested the combined prognostic power of three well-established biomarkers: brain natriuretic peptide (BNP), C-reactive protein (CRP), and asymmetric dimethyl arginine (ADMA). The independent prognostic value of individual and combined biomarkers was estimated in separate Cox models, including standard risk factors in dialysis patients and comorbidities. RESULTS: When the prediction power of the three biomarkers was evaluated individually, BNP, ADMA, and CRP added significant predictive value (P< or = 0.01) to all-cause and cardiovascular mortality models and the explanatory gain attributable to these biomarkers were of similar degree (ranging from 3.3% to 5.7%). When the biomarkers were evaluated jointly, a score based on the BNP-CRP combination, increased by 9.9% (all-cause) and by 10.5% (cardiovascular) the explained mortality variance of standard Cox models and such gain in power was similar to that achieved by the CRP-ADMA combination (all-cause death 9.0% and cardiovascular death 8.4%). Of note, the explanatory gain derived by the simultaneous use of the three biomarkers was very similar (all-cause death 11.6% and cardiovascular death 10.5%) to that achieved by the use of two biomarkers. CONCLUSION: These findings indicate a potential role for CRP, BNP, and ADMA to be incorporated into diagnostic and therapeutic strategies aimed at detection and treatment of atherosclerotic complications and at preventing heart failure in the dialysis population.

Adult↗

The use of histologically defined specific biomarkers in drug development with special reference to the glutathione S-transferases.

Failure of drug candidates late in development is very expensive. This can be reduced by using more specific biomarkers of effect and toxicity during the preclinical and development testing. However, traditional toxicity tests have not been developed to study toxicology and so may lack sufficient sensitivity and specificity hence the search for new biomarkers using the many "-omics" technologies. Important aspects of useful biomarkers are that their origin is known and localised so that one knows what is being observed. Furthermore, biomarkers with a localised origin are less likely to be subject to background variation and have a wider dynamic range. This paper will discuss how using biomarkers with a known cellular origin, toxic effects can be found earlier and at lower doses of compound.

Adaptation, Biological↗

Clinical utility of laboratory testing in women with osteoporosis.

Clinicians regularly order laboratory tests in women with osteoporosis to assess if an underlying medical condition is contributing to bone loss. To determine which laboratory tests are associated with osteoporosis we conducted a secondary analyses of data collected as part of the Fracture Intervention Trial (FIT), which included 15,316 postmenopausal women. Women had tests of liver and kidney function, mineral metabolism, electrolytes and complete blood count, femoral neck and total body BMD and spinal radiographs. The prevalence of abnormal tests in women with osteoporosis compared to women without was not different, except for low TSH (<0.5 IU/ml). Among women with and without osteoporosis at the femoral neck the prevalence of low TSH was 4.9% (95% CI: 4.4-5.5) and 3.7% (95% CI: 3.3-4.1), respectively, yielding a positive likelihood ratio of 1.2 (95% CI: 1.1-1.3). We observed similar results for women with vertebral fractures compared to women without vertebral fractures; positive likelihood ratio of 1.4 (95% CI: 1.3-1.6). Our data suggests that when assessing healthy women with osteoporosis ordering a routine panel of laboratory tests is not useful but measuring TSH may be informative.

Aged↗

Isoform-specific quantification of metallothionein in the terrestrial gastropod Helix pomatia. II. A differential biomarker approach under laboratory and field conditions.

The two function-specific metallothionein (MT) isoforms characterized from the midgut gland and mantle tissue of Helix pomatia differ substantially in their metal-binding preferences, as well as molecular and biochemical features. These differences make them potential candidates for biomarker studies based on a differential, isoform-specific approach. To prove this hypothesis, induction experiments with two metals (Cd and Cu) that are normally bound by the two isoforms were compared with a range of organic chemicals and physical stressors under laboratory conditions to test the responsiveness of the two isoforms to the stressors applied. In addition, field studies were conducted with Roman snails and substrate samples collected from different metal-contaminated sites in Austria to test the suitability of the two isoforms as biomarkers under field conditions. The results of these combined laboratory and field studies confirmed the validity of the biomarker approach with the two metal- and tissue-specific isoforms. It is demonstrated that the Cd-binding MT specifically and exclusively responds to Cd exposure by increasing concentrations, whereas the Cu-binding MT isoform decreases in its concentration upon exposure to physical stress (X-ray irradiation and cold). This suggests researchers should adopt, under certain preconditions, a dual biomarker approach by combining the simultaneous quantification of Cd-MT concentrations in the midgut gland as a biomarker for Cd pollution and of Cu-MT concentration in the mantle as a biomarker for the impairment of snails by additional physical stressors.

Animals↗

Direct cancer tissue proteomics: a method to identify candidate cancer biomarkers from formalin-fixed paraffin-embedded archival tissues.

Successful treatment of multiple cancer types requires early detection and identification of reliable biomarkers present in specific cancer tissues. To test the feasibility of identifying proteins from archival cancer tissues, we have developed a methodology, termed direct tissue proteomics (DTP), which can be used to identify proteins directly from formalin-fixed paraffin-embedded prostate cancer tissue samples. Using minute prostate biopsy sections, we demonstrate the identification of 428 prostate-expressed proteins using the shotgun method. Because the DTP method is not quantitative, we employed the absolute quantification method and demonstrate picogram level quantification of prostate-specific antigen. In depth bioinformatics analysis of these expressed proteins affords the categorization of metabolic pathways that may be important for distinct stages of prostate carcinogenesis. Furthermore, we validate Wnt-3 as an upregulated protein in cancerous prostate cells by immunohistochemistry. We propose that this general strategy provides a roadmap for successful identification of critical molecular targets of multiple cancer types.

Amino Acid Sequence↗

Hydrogen sulphide production tests and the detection of groundwater faecal contamination by septic seepage.

The 'H2S test' is being advanced for microbiological water quality testing where conventional coliform based methods are impractical or too expensive. It involves ambient temperature incubation of water samples with nutrient formulated to generate hydrogen sulphide when 'faecal' bacteria are present. Recently a WHO review identified several concerns including the limited number of comparative studies, formulation variability, and false positives and negatives. In response we have compared the H2S test's ability to detect and quantify faecal contamination in an aquifer impacted by septic tank leachfields with measurements obtained concurrently using conventional bacterial indicators, coliphages, faecal sterol biomarkers, Cryptosporidium and Giardia. Like these other analytes, H2S testing detected a contamination gradient ranging from high (septic liquid) to moderate (exfiltration zones), to background (e.g. domestic bores), corresponding to indicator removal + dilution by factors > 10(6). Presence/absence tests could not distinguish between heavily and slightly contaminated waters, whereas multi-tube testing (e.g. 10 x 10 mL arrays) did. It was concluded that while the WHO review concerns are justified, the H2S test performance shows promise in sanitary survey work, can be improved by employing an mpn approach and has potential to aid in the protection of source water and identifying contaminated groundwater.

Environmental Monitoring↗

Noninvasive magnetic resonance spectroscopic imaging biomarkers to predict the clinical grade of pediatric brain tumors.

The diagnosis and therapy of childhood brain tumors, most of which are low grade, can be complicated because of their frequent adjacent location to crucial structures, which limits diagnostic biopsy. Also, although new prognostic biomarkers identified by molecular analysis or DNA microarray gene profiling are promising, they too depend on invasive biopsy. Here, we test the hypothesis that combining information from biologically important intracellular molecules (biomarkers), noninvasively obtained by proton magnetic resonance spectroscopic imaging, will increase the diagnostic accuracy in determining the clinical grade of pediatric brain tumors. We evaluate the proton magnetic resonance spectroscopic imaging exams for 66 children with brain tumors. The intracellular biomarkers for choline-containing compounds (Cho), N-acetylaspartate, total creatine, and lipids and/or lactate were measured at the highest Cho region and normalized to the surrounding healthy tissue total creatine. Neuropathological grading was done with WHO criteria. Normalized Cho and lipids and/or lactate were elevated in high-grade (n = 23) versus low-grade (n = 43) tumors, which multiple logistic regression confirmed are independent predictors of tumor grade (for Cho, odds ratio 24.8, P < 0.001; and for lipids and/or lactate, odds ratio 4.4, P < 0.001). A linear combination of normalized Cho and lipids and/or lactate that maximizes diagnostic accuracy was calculated by maximizing the area under the receiver operating characteristic curve. Proton magnetic resonance spectroscopic imaging, although not a proxy for histology, provides noninvasive, in vivo biomarkers for predicting clinical grades of pediatric brain tumors.

Aspartic Acid↗

Screening for prostate cancer: opportunities and challenges.

Prostate cancer screening with PSA and with digital rectal examination isa reality in the United States. Regardless of recent observations regarding the complexities of PSA interpretation, millions of U.S. men expect an annual PSA test and physicians have come to rely on the test, in combination with digital rectal examination, to assess for prostate cancer risk. What has become evident is that PSA can no longer be interpreted dichotomously as a simple yes or no. The test reflects a range of risk and PSA value must be merged with other risk factors of an individual man including ethnicity, family history, as well as the individual's risk aversion to complications from prostate cancer. The future of prostate cancer screening will be built upon incorporation of new biomarkers to the prediction of risk of disease. As these markers move forward in testing, it will no longer be acceptable to move these into clinical usage without formal validation studies and, because of the high frequency of prostate cancer in the general male population, these validation studies will almost certainly have to include measures of prognosis. It is the holy grail of cancer biomarker development to acquire a test that is positive in the man with clinically-aggressive prostate cancer but is negative in both the patient without disease and in the man with disease that will be of no clinical consequence over his lifetime.

Adenocarcinoma↗